Lupus (systemic lupus erythematosus, SLE) is a chronic autoimmune disease characterized by the presence of activated T and B cells, autoantibodies and chronic inflammation that attacks various parts of the body including the joints, skin, kidneys, CNS, cardiac tissue and blood vessels. In severe cases, antibodies are deposited in the cells (glomeruli) of the kidneys, leading to inflammation and possibly kidney failure, a condition known as lupus nephritis.
Although the cause of lupus remains unknown, manifestations of the disease have been linked to genetic polymorphisms, environmental toxins and pathogens (Morel 2010; Fairhurst, Wandstrat et al. 2006). In addition, gender, hormonal influences and cytokine dysregulation have been tightly linked to the development of lupus (Aringer and Smolen 2004; Smith-Bouvier, Divekar et al. 2008). Lupus affects nine times as many women as men. It may occur at any age, but appears most often in people between the ages of 10 and 50 years. African Americans and Asians are affected more often than people from other races.
There is no cure for lupus. Current treatments for lupus are aimed at controlling symptoms and are limited to toxic and immunosuppressive agents with severe side-effects such as high dose glucocorticoids and/or hydroxchloroquine. Severe disease (e.g., patients that have signs of renal involvement) require more aggressive drugs including mycophenolate mofetil (MMF), azathioprine (AZA) and/or cyclophosphamide (CTX) (Bertsias and Boumpas 2008). CTX, AZA and MMF are very toxic and immunosuppressive, and only 50% of treated patients enter complete remission, with relapse rates up to 30% over a 2-year period.
Proteasome inhibitors have shown some potential as treatments for lupus. In recent studies, bortezomib—the only FDA approved proteasome inhibitor (marketed by Millennium Pharmaceuticals under the trade name Velcade® for multiple myeloma)—markedly prolonged survival of lupus prone NZB/W F1 mice as compared to vehicle, and also significantly reduced proteinuria and improved renal pathology (Neubert, Kirsten et al., 2008; Lee, S. W. and Kim, B. S., 2010). In a more limited study (6 control animals, 5 on drug), bortezomib also significantly improved survival of MRL/lpr mice (p=0.03) (Neubert, Kirsten et al., 2008). In a case study of a woman with both multiple myeloma and lupus, bortezomib combined with prednisolone improved the patient's lupus symptoms (Fröhlich, Karen et al., 2010). An impediment to using bortezomib as a treatment for lupus is that bortezomib is associated with serious side effects such as polyneuropathy, thrombocytopenia and gastrointestinal complications (Lee, S. W. and Kim, B. S., 2010; Fröhlich, Karen et al., 2010).
A need exists for new treatments for lupus, including lupus nephritis.